Experimental
(13E,15S)-15-Hydroxy-11-oxoprosta-9,13-dien-1-oic acid
methyl ester (16)†
A degassed (argon) solution of compound (14) (17 mg) in anhy-
drous acetonitrile (1.7 ml) was cooled to Ϫ20 ЊC and treated
with an aqueous solution of hydrofluoric acid (40% w/w,
0.22 ml). After stirring for 9 h at Ϫ20 ЊC, ethyl acetate (10 ml)
and sodium hydrogen carbonate (8% aqueous solution, 30 ml)
were added. The organic layer was separated and the aqueous
solution washed with ethyl acetate (15 ml). The combined
organic extracts were washed with sodium hydrogen carbonate
(8% aqueous solution, 2 × 20 ml). The aqueous extracts were
back-extracted with ethyl acetate (2 × 20 ml). The organic
extracts were combined and dried (MgSO4). Filtration and
evaporation of the solvent gave a crude product which was
purified by chromatography over silica [eluent ethyl acetate in
hexane (2:3)] to give the title compound (16) (8.1 mg, 88%) as a
colourless oil. νmax (neat) 3590, 1730, 1700, 1585 cmϪ1. [α]D25 91.4
(c 0.7, CHCl3). δH (300 MHz, CDCl3) 0.88 (3H, t, J 7.0,
CH2CH3), 1.18–1.66 (19H, m, 9 × CH2 and OH), 2.31 (2H, t, J
7.5, CH2CO), 2.62 (1H, dd, J 2.75 and 7.1, H-12), 2.75 (1H, m,
H-8), 3.67 (3H, s, OCH3), 4.10 (1H, dt, J 6.5 and 6.5, H-15),
5.57 (1H, dd, J 7.1 and 15.4, H-13), 5.69 (1H, dd, J 6.5 and 15.4,
H-14), 6.14 (1H, dd, J 2.2 and 5.6, H-10), 7.59 (1H, dd, J 2.2
and 5.6, H-9). δC (75 MHz, CDCl3) 13.95 (CH3), 22.57, 24.79,
25.06, 27.21, 28.91, 29.23, 31.72, 33.95, 33.96, 37.07 (all CH2),
48.22 (OCH3), 51.45, 55.23, 72.67, 127.14, 132.49, 136.93,
Scheme 2 Reagents and conditions: i) Ac2O, DMAP, pyridine, 92%; ii)
CH3CO2H–THF–H2O (3:1:1), 48 h, room temp., 79%; iii) Dess–
Martin reagent, CH2Cl2, room temp., 89%; iv) Jones’ reagent, KF, acet-
one, 0 ЊC, 87%; v) NaHCO3, MeOH, room temp., 82%; vi) aq. HF
(40% w/w), CH3CN, Ϫ20 ЊC, (a): 77% yield, (b): 88% yield.
with a mixture of acetic acid, THF and water gave compound
(13) (79%) as the only identifiable product. Oxidation of this
compound with Dess–Martin periodinane9 gave the PG-D1
derivative (14) in 89% yield. Alternatively, oxidation of diester
(12) with KF in Jones’ reagent (CrO3, H2SO4)10 provided the
β-acetoxyketone (14) directly in 87% yield. Thereafter treat-
ment of the β-acetoxyketone with sodium hydrogen carbonate
in methanol afforded the desired cyclopentenone (15) in 82%
yield.
Attempted desilylation of the enone (15) with tert-butoxide
in DMF11 or with tetra-n-butylammonium fluoride buffered
with acetic acid12 led to the formation of PG-J1 methyl ester
(16) together with the inseparable isomeric compound (17).
166.71 (all CH), 174.20, 208.88 (C᎐O). Found (CI): (M ϩ
᎐
NH4)ϩ 368.27930. C21H38NO4 requires Mϩ 368.28008.
Acknowledgements
We thank the Eden Fund (University of Liverpool) for financial
support during the course of this work. Other support from
AstraCharnwood, Loughborough, UK, and the advice of
Dr Anthony Ingall are gratefully acknowledged.
Notes and references
† The IUPAC name for 16 is methyl 7-{5-[(1E,3S)-oct-1-enyl]-4-
oxocyclopent-2-en-1-yl}heptanoate.
1 S. M. Roberts and F. Scheinmann, New Synthetic Routes to Prosta-
glandins and Thromboxanes, Academic Press, London, 1982.
2 P. W. Collins and S. W. Djuric, Chem. Rev., 1993, 93, 1533.
3 M. A. Tius, H. Hu, J. K. Kawakami and J. Busch-Petersen, J. Org.
Chem., 1998, 63, 5971.
4 M. G. Santoro, Trends Microbiol., 1997, 5, 276; A. Rossi, G. Elia
and M. G. Santoro, Proc. Natl. Acad. Sci. U.S.A., 1997, 94, 746;
M. G. Santoro, Leukotrienes, 1998, 95; A. Rossi, G. Elia and M. G.
Santoro, J. Biol. Chem., 1998, 273, 1; A. De Marco, A. Caratolli,
C. Rozera, D. Fortini, C. Giorgi, G. Belardo, C. Amici and M. G.
Santoro, Eur. J. Biochem., 1998, 256, 334.
5 C. R. Johnson and M. P. Braun, J. Am. Chem. Soc., 1993, 115, 11014;
C. R. Johnson, J. P. Adams, M. P. Braun, C. B. B. Senanayake, P. M.
Wovkulichand, M. R. Uskokovic, Tetrahedron Lett., 1992, 33, 917.
6 M. Schlosser and J. Hartmann, Angew. Chem., Int. Ed. Engl., 1973,
85, 544; B. H. Lipshutz, in Organometallics in Synthesis - A Manual,
ed. M. Schlosser, Wiley and Sons, New York, 1994, p. 319.
7 Conditions reported to cleave TBS ethers in the presence of TBDPS
ethers include CH3CO2H–THF–H2O (3:1:1); tBuOK–DMF;
HCl (2 M)–THF; LiCl–H2O–DMF. All these methods failed to
desilylate selectively in the case of compound (10).
However treatment of the enone (15) with 40% aqueous hydro-
gen fluoride in acetonitrile at Ϫ20 ЊC gave the desired product
(16) cleanly in 77% yield. Gratifyingly, when the acetate (14)
was reacted under the same conditions, PG-J1 methyl ester (16)
was obtained as the sole product in 88% yield.
In the biological tests PG-J1 methyl ester showed potent, sub-
micromolar activity against Sendai 37RC virus (Table 1). The
mechanism of action is unlikely to be specific to Sendai virus;
related studies into the antiviral activity of various prosta-
glandin analogues are on-going and will be reported shortly.
8 A. S.-Y. Lee, H.-C. Yeh, M.-K. Yeh and M.-H. Tsai, J. Chin. Chem.
Soc. (Taipei), 1995, 42, 919.
Table 1 Activity of some prostaglandins against Sendai virus
9 D. B. Dess and J. C. Martin, J. Am. Chem. Soc., 1991, 113, 7277.
10 A. J. Pearson, Y.-S. Lai, W. Lu and A. A. Pinkerton, J. Org. Chem.,
1989, 54, 3882; H.-J. Liu and I.-S. Han, Synth. Commun., 1985, 12,
759.
Activity
Compound
ID50 (µM)a
PG-A2
PG-A1
PG-J2
PG-J1 methyl ester
3.0
1.5
1.0
0.5
11 C. Negron, F. Vasquez and G. Calderon, Synth. Commun., 1998, 28,
3021.
12 C. M. Hayward, D. Yohannes and S. J. Danishefsky, J. Am. Chem.
Soc., 1993, 115, 9346; A. B. Smith III, S. Y. Chen, F. C. Nelson, J. M.
Reichert and B. A. Salvatore, J. Am. Chem. Soc., 1997, 119, 10935.
a ID50: concentration of test compound necessary to reduce virus load
by 50%.
Communication 9/03813B
2438
J. Chem. Soc., Perkin Trans. 1, 1999, 2437–2438